Neurotransmitters are in charge of transmission of stimulation by nerves and functions of major organs. Neurotransmitters are classified as cholinergic nervous system, releasing acetylcholine by the stimulation in the central nervous system and peripheral nervous system, adrenergic nervous system, releasing noradrenalin, and other neurotransmitters significant in the central nervous system such as dopamine, serotonine, inhibitory GABA (γ-amino butyric acid). Among those, serotonine nervous system is closely related to mental illnesses such as concerns, anxiety or depression. Schizophrenic or patients with dimentia have noticeably decreased dispersion of receptors of the neurotransmitters. Serotonine in brain is known as an important neuro transmitting network controlling behaviors caused by concerns, anxiety, and physical functions to regulate various physiological functions and mental status.
In the central nervous system, serotonine (5-HT) is related with factors of many diseases, especially mental illnesses such as depression, anxiety, schizophrenia, eating disorders, obsessive compulsive disorder, migraine, panic disorder. In recent, due to the development of pharmacology, molecular biology, genetics relating serotonine nervous system, enhanced medicinal therapies to cure a certain disease of central nervous system are now available. The general treatment for such diseases for now is to regulate physiological activities of serotonine materials.
A major metabolite of venlafaxine, O-desmethylvenlafaxine (hereinafter, referred to as “ODV”), has been shown to inhibit serotonine and norepinephrine reuptake (Klamerus, K. J. et al, “Introduction of the Composite Parameter to the Pharmacokinetics of Venlafaxine and its Active O-Desmethyl Metabolite”, J. Clin. Pharmacol. 32:716-724 1992). Therefore, ODV is used to treat diseases of central nervous system, especially, depression or generalized anxiety disorder (see U.S. Pat. No. 5,916,923; U.S. Pat. No. 6,444,708; U.S. Pat. No. 6,274,171; U.S. Pat. No. 6,403,120; U.S. Pat. No. 6,419,958; U.S. Pat. No. 6,310,101). Venlafaxine hydrochloride tablets are available in the market under the product name, EFFEXOR®.
ODV, chemically named 1-(2-(dimethylamino)-1-(4-phenol)ethyl)cyclohexanol, is exemplified as fumarate salt in U.S. Pat. No. 4,535,186. However, the fumarate salt of ODV has unsuitable physicochemical and permeability characteristics. ODV is also exemplified as a free base in International Patent Publication No. WO 00/32555.
The prior art of ODV will be explained below.
Succinate form of ODV is disclosed in U.S. Pat. No. 6,673,838. Succinate monohydrate form of ODV is widely known as sustained-release tablets to relieve side effects such as nausea, vomit, diarrhea or stomachache.
In International Patent Publication No. WO 02/064543 A2, dosage form representing the use of hydroxypropyl methyl cellulose (HPMC) as hydrogel matrix is disclosed.
In U.S. Pat. No. 4,535,186, (R/S)-1-(2-(dimethylamino)-1-(4-methoxyphenyl)ethyl)cyclohexanol and its metabolite, 1-(2-(dimethylamino)-1-(4-methoxyphenyl)ethyl)cyclohexanol and 1-(1-(4-methoxyphenyl)-2-(methylamino)ethyl)cyclohexanol are disclosed.
In U.S. Pat. No. 5,530,013, the use of venlafaxine to induce improved cognitive power is disclosed.
In U.S. Pat. No. 5,506,270, the use of venlafaxine to treat hypothalamic amenorrhea of women with no depression is disclosed.
In U.S. Pat. No. 5,788,986 and U.S. Pat. No. 5,554,383, the use of serotonine reuptake inhibitor to change the habit of dogs is disclosed.
In U.S. Pat. No. 6,348,494, ether of ODV, especially, O-α-acyloxyalkyl ether of 4-(2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl)phenol, its preparation method, and pharmaceutical composition and use thereof are disclosed.
However, the above-mentioned materials have problems of low solubility in water.
Accordingly, the present inventors tried to develop ODV derivatives which have high water solubility, but does not affect ODV activity level, and completed the present invention by confirming that the compound of {4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl)ethyl]phenoxy}phosphate has high water solubility and similar activity compared to other salt of ODV.